Clinical, laboratory and genetic characteristics of VEXAS syndrome: a study on behalf of GESMD

VEXAS syndrome ('Vacuoles', 'E1 enzyme', 'X-linked', 'Autoinflammatory' and 'Somatic') is a rare autoinflammatory disorder caused by somatic mutations in the UBA1 (ubiquitin-like modifier-activating enzyme 1) gene whose treatment and prognosis remain poorly understood. The GESMD group (Grupo Español de Síndromes Mielodisplásicos) conducted a retrospective multicenter study of 40 male patients (median age 74 years), to analyze clinical and biological features, treatments, responses, prognosis and outcomes. UBA1 mutations were present in all patients, the c.209T>A mutation-previously reported by García-Escudero et al. as a novel and presumably causative variant in VEXAS syndrome-was associated with older age at diagnosis, a lower frequency of lymph node involvement, and milder anemia. However, these data should be validated in larger cohorts. Overall, 58 treatment lines were administered, including corticosteroids, JAK inhibitors, anti-IL1 and anti-IL6 agents, hypomethylating agents (HMA), and other immunomodulators. Corticosteroid therapy led to rapid early improvement but limited by dependence and tapering difficulties. HMA showed a gradual and sustained increase in global, clinical, and biological responses over time, reaching high proportions of improvement at 12 months despite being used predominantly in more refractory patients (83.3% of patients showed a global response, including 50.0% of complete responses and 33.3% of partial responses). The median time to next treatment or death (TNT-D) was 11 months. Treatment discontinuation occurred in 25 of 58 lines (43.1%), mainly due to lack of efficacy, toxicity, or the need for steroid-sparing. Overall survival data remained immature due to the limited number of events, although gastrointestinal involvement appeared associated with poorer prognosis (P = 0.018), while achieving clinical or biological response correlated with better survival (P = 0.001 and P = 0.003). This study provides a detailed characterization of the Spanish VEXAS cohort, highlighting evolving therapeutic trajectories and the potential role of HMA, and underscores the need for larger prospective studies to define long-term outcomes.